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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite Anti-TNFα Therapy

    Summary
    EudraCT number
    2010-022243-38
    Trial protocol
    LT   DE   GB   AT   ES   PT   BE   IT   NL  
    Global end of trial date
    12 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jan 2017
    First version publication date
    05 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNTO136ARA3003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01606761
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis (RA) in subjects with moderately to severely active RA who were refractory or intolerant to anti-tumor necrosis factor (anti-TNF) agents.
    Protection of trial subjects
    The safety assessments included adverse events, laboratory measurements (hematology, serum chemistry, and urinalysis), vital sign measurements, and physical examinations. Adverse events were monitored throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Scientific research
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 19
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 116
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Lithuania: 16
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 76
    Country: Number of subjects enrolled
    Puerto Rico: 8
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    United States: 445
    Worldwide total number of subjects
    878
    EEA total number of subjects
    181
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    684
    From 65 to 84 years
    194
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 878 subjects (placebo [n=294], sirukumab 50 mg every 4 week (q4w) [n=292], and sirukumab 100 mg every 2 week q2w [n=292]) were randomized and included in the study.

    Period 1
    Period 1 title
    Placebo Controlled Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received matching placebo every 2 week (q2w) until either early escape (EE) at Week 18, or crossover (CO) at Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received matching placebo subcutaneously (SC) q2w until either early escape (EE) at Week 18, or crossover (CO) at Week 24.

    Arm title
    Sirukumab 50 mg
    Arm description
    Subjects received Sirukumab 50 mg SC at Week 0, 4 and q4w up to Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab 50 milligram (mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Sirukumab 50 mg SC Week 0, 4 and q4w up to Week 24.

    Arm title
    Sirukumab 100 mg
    Arm description
    Subjects received Sirukumab 100 mg SC at Week 0, 2 and q2w up to Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Sirukumab 100 mg SC at Week 0, 2 and q2w up to Week 24.

    Number of subjects in period 1
    Placebo Sirukumab 50 mg Sirukumab 100 mg
    Started
    294
    292
    292
    Completed
    252
    237
    246
    Not completed
    42
    55
    46
         Physician decision
    -
    3
    1
         Other
    3
    7
    5
         Lack of efficacy
    15
    14
    8
         Adverse events
    11
    19
    21
         Consent withdrawn by subject
    12
    9
    9
         Lost to follow-up
    1
    3
    2
    Period 2
    Period 2 title
    Active Controlled Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo to 50 mg q4w due to EE or CO
    Arm description
    Subjects who received matching placebo in the placebo controlled period were re-randomized (due to early escape [EE] at Week 18 or crossed over [CO] at Week 24) to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab 50 milligram (mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received sirukumab 50 mg SC injection every 4 week (q4w) up to Week 52.

    Arm title
    Sirukumab 50 mg
    Arm description
    Subjects continued to receive sirukumab 50 mg SC q4w from Week 24 up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab 50 milligram (mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received sirukumab 50 mg SC injection every 4 week (q4w) from Week 24 up to Week 52.

    Arm title
    Placebo to 100 mg q2w due to EE or CO
    Arm description
    Subjects who received matching placebo in the placebo controlled period were re-randomized (due to EE at Week 18 or CO at Week 24) to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Sirukumab 100 mg SC at q2w from Week 24 up to Week 52.

    Arm title
    Sirukumab 100 mg q2w
    Arm description
    Subjects continued to receive sirukumab 100 mg SC q2w from Week 24 up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Sirukumab 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Sirukumab 100 mg SC q2w from Week 24 up to Week 52.

    Number of subjects in period 2
    Placebo to 50 mg q4w due to EE or CO Sirukumab 50 mg Placebo to 100 mg q2w due to EE or CO Sirukumab 100 mg q2w
    Started
    126
    237
    126
    246
    Completed
    109
    204
    106
    212
    Not completed
    17
    88
    20
    80
         Death
    1
    -
    -
    2
         Physician decision
    -
    4
    -
    2
         Other
    2
    8
    2
    10
         Lack of efficacy
    10
    27
    3
    15
         Adverse events
    3
    29
    15
    36
         Consent withdrawn by subject
    -
    16
    -
    12
         Lost to follow-up
    1
    4
    -
    3
    Joined
    0
    55
    0
    46
         Discontinued prior to Week 24
    -
    55
    -
    46

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received matching placebo every 2 week (q2w) until either early escape (EE) at Week 18, or crossover (CO) at Week 24.

    Reporting group title
    Sirukumab 50 mg
    Reporting group description
    Subjects received Sirukumab 50 mg SC at Week 0, 4 and q4w up to Week 24.

    Reporting group title
    Sirukumab 100 mg
    Reporting group description
    Subjects received Sirukumab 100 mg SC at Week 0, 2 and q2w up to Week 24.

    Reporting group values
    Placebo Sirukumab 50 mg Sirukumab 100 mg Total
    Number of subjects
    294 292 292 878
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    228 225 230 683
        From 65 to 84 years
    66 67 62 195
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    55.4 ± 12.28 55.8 ± 11.89 55 ± 12.31 -
    Title for Gender
    Units: subjects
        Female
    240 232 240 712
        Male
    54 60 52 166

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received matching placebo every 2 week (q2w) until either early escape (EE) at Week 18, or crossover (CO) at Week 24.

    Reporting group title
    Sirukumab 50 mg
    Reporting group description
    Subjects received Sirukumab 50 mg SC at Week 0, 4 and q4w up to Week 24.

    Reporting group title
    Sirukumab 100 mg
    Reporting group description
    Subjects received Sirukumab 100 mg SC at Week 0, 2 and q2w up to Week 24.
    Reporting group title
    Placebo to 50 mg q4w due to EE or CO
    Reporting group description
    Subjects who received matching placebo in the placebo controlled period were re-randomized (due to early escape [EE] at Week 18 or crossed over [CO] at Week 24) to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 52.

    Reporting group title
    Sirukumab 50 mg
    Reporting group description
    Subjects continued to receive sirukumab 50 mg SC q4w from Week 24 up to Week 52.

    Reporting group title
    Placebo to 100 mg q2w due to EE or CO
    Reporting group description
    Subjects who received matching placebo in the placebo controlled period were re-randomized (due to EE at Week 18 or CO at Week 24) to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 52.

    Reporting group title
    Sirukumab 100 mg q2w
    Reporting group description
    Subjects continued to receive sirukumab 100 mg SC q2w from Week 24 up to Week 52.

    Primary: Percentage of Subjects Achieving American College of Rheumatology (ACR)20 Response at Week 16

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    End point title
    Percentage of Subjects Achieving American College of Rheumatology (ACR)20 Response at Week 16
    End point description
    The ACR 20 Response is defined as greater than or equal to (>=) 20 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=20 percent improvement in 3 of following 5 assessments: patient's assessment of pain using Visual Analog Scale (VAS; 0-10 millimeter [mm], 0 mm=no pain and 10 mm=worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas. The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum C-Reactive Protein (CRP). Efficacy full analysis set included all subjects who were randomized into the study.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    294
    292
    292
    Units: Percentage of subjects
        number (not applicable)
    24.1
    40.1
    45.2
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Sirukumab 50 mg
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.085
         upper limit
    0.232
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Sirukumab 100 mg
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.136
         upper limit
    0.285

    Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24

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    End point title
    Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24
    End point description
    The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping and activities of daily living). Responses in each functional area are scored from 0 to 3 (0=no difficulty and 3=inability to perform a task in that area). Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Here, 'N' (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint. Efficacy full analysis set included all subjects who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    294
    291
    292
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.12 ± 0.491
    -0.31 ± 0.543
    -0.33 ± 0.526
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Sirukumab 50 mg
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.251
         upper limit
    -0.088
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Sirukumab 100 mg
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -0.194
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.275
         upper limit
    -0.112

    Secondary: Percentage of Subjects Achieving American College of Rheumatology (ACR) 50 Response at Week 24

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    End point title
    Percentage of Subjects Achieving American College of Rheumatology (ACR) 50 Response at Week 24
    End point description
    The ACR 50 Response is defined as >=50 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=50 percent improvement in 3 of following 5 assessments: patient's assessment of pain using VAS (0-10 mm, 0 mm=no pain and 10 mm=worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by HAQ-DI and serum CRP. Efficacy full analysis set included all subjects who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    294
    292
    292
    Units: percentage of subjects
        number (not applicable)
    8.8
    20.9
    21.6
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Sirukumab 50 mg
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.064
         upper limit
    0.177
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Sirukumab 100 mg
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    0.127
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    0.184

    Secondary: Percentage of Subjects With Disease Activity Index Score 28 (CRP) Remission at Week 24

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    End point title
    Percentage of Subjects With Disease Activity Index Score 28 (CRP) Remission at Week 24
    End point description
    The Disease Activity Index Score 28 (DAS28) based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of less than (<) 2.6 at any study visit. Efficacy full analysis set included all subjects who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Sirukumab 50 mg Sirukumab 100 mg
    Number of subjects analysed
    294
    292
    292
    Units: percentage of Subjects
        number (not applicable)
    8.2
    19.2
    21.6
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Sirukumab 50 mg v Placebo
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.055
         upper limit
    0.165
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Sirukumab 100 mg
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    0.134
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.078
         upper limit
    0.191

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 52
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Week (W) 24-Placebo
    Reporting group description
    Subjects received matching placebo every 2 week (q2w) until either early escape (EE) at Week 18, or crossover (CO) at Week 24.

    Reporting group title
    W24-Placebo to 50 mg q4w due to EE or CO
    Reporting group description
    Subjects who received matching placebo in the placebo controlled period and were re-randomized (due to early escape [EE] at Week 18 or crossed over [CO] at Week 24) to subcutaneous (SC) sirukumab 50 mg q4w dose regimen.

    Reporting group title
    W24-Sirukumab 50 mg q4w
    Reporting group description
    Subjects received Sirukumab 50 mg SC at Week 0, 4 and q4w up to Week 24.

    Reporting group title
    W24-Placebo to 100 mg q2w due to EE or CO
    Reporting group description
    Subjects who received matching placebo in the placebo controlled period and were re-randomized (due to early escape [EE] at Week 18 or crossed over [CO] at Week 24) to subcutaneous (SC) sirukumab 100 mg q2w dose regimen.

    Reporting group title
    W24-Sirukumab 100 mg q2w
    Reporting group description
    Subjects received sirukumab 100 mg SC at Week 0, 2 and q2w up to Week 24.

    Reporting group title
    W52-Placebo to 50 mg q4w due to EE or CO
    Reporting group description
    Subjects who received matching placebo in the placebo controlled period and were re-randomized (due to early escape [EE] at Week 18 or crossed over [CO] at Week 24) to receive subcutaneous (SC) sirukumab 50 mg q4w dose regimen up to Week 52.

    Reporting group title
    W52-Sirukumab 50 mg q4w
    Reporting group description
    Subjects received Sirukumab 50 mg SC q4w up to Week 52.

    Reporting group title
    W52-Placebo to 100 mg q2w due to EE or CO
    Reporting group description
    Subjects who received matching placebo in the placebo controlled period and were re-randomized (due to early escape [EE] at Week 18 or crossed over [CO] at Week 24) to receive subcutaneous (SC) sirukumab 100 mg q4w dose regimen up to Week 52.

    Reporting group title
    W52-Sirukumab 100 mg q2w
    Reporting group description
    Subjects received Sirukumab 100 mg SC q2w up to Week 52.

    Serious adverse events
    Week (W) 24-Placebo W24-Placebo to 50 mg q4w due to EE or CO W24-Sirukumab 50 mg q4w W24-Placebo to 100 mg q2w due to EE or CO W24-Sirukumab 100 mg q2w W52-Placebo to 50 mg q4w due to EE or CO W52-Sirukumab 50 mg q4w W52-Placebo to 100 mg q2w due to EE or CO W52-Sirukumab 100 mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 294 (5.10%)
    0 / 46 (0.00%)
    28 / 292 (9.59%)
    3 / 48 (6.25%)
    22 / 292 (7.53%)
    7 / 124 (5.65%)
    49 / 292 (16.78%)
    16 / 126 (12.70%)
    37 / 292 (12.67%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
    1
    1
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent Claudication
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosed Varicose Vein
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    1 / 124 (0.81%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast Cancer Metastatic
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Chondroma
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Adenocarcinoma
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoproliferative Disorder
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    1 / 124 (0.81%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Adenocarcinoma
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food Allergy
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Missed
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    1 / 124 (0.81%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    2 / 292 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Dislocation
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    2 / 292 (0.68%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired Healing
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    2 / 292 (0.68%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    2 / 292 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic Fracture
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    2 / 292 (0.68%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Enzyme Abnormal
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    1 / 48 (2.08%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Morganella Test Positive
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    3 / 292 (1.03%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal Oedema
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal Discomfort
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Normochromic Normocytic Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid Artery Stenosis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    1 / 124 (0.81%)
    2 / 292 (0.68%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Diabetic Neuropathy
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    1 / 48 (2.08%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal Fissure
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    1 / 124 (0.81%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular Perforation
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum Intestinal
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer Perforation
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecal Incontinence
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Perforation
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis Erosive
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Pseudocyst
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus Ureteric
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Eruption
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthrofibrosis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot Deformity
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    2 / 292 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    2 / 292 (0.68%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    1 / 124 (0.81%)
    3 / 292 (1.03%)
    1 / 126 (0.79%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    2 / 294 (0.68%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    1 / 124 (0.81%)
    3 / 292 (1.03%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Nodule
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Necrosis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    1 / 124 (0.81%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess Jaw
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alpha Haemolytic Streptococcal Infection
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis Infective
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    2 / 292 (0.68%)
    1 / 48 (2.08%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    2 / 292 (0.68%)
    2 / 126 (1.59%)
    2 / 292 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 1
    0 / 0
    0 / 0
    1 / 2
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic Abscess
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    2 / 292 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising Fasciitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    1 / 292 (0.34%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    2 / 292 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    4 / 292 (1.37%)
    0 / 48 (0.00%)
    3 / 292 (1.03%)
    0 / 124 (0.00%)
    5 / 292 (1.71%)
    0 / 126 (0.00%)
    5 / 292 (1.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 4
    0 / 0
    3 / 3
    0 / 0
    4 / 5
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    1 / 126 (0.79%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    1 / 292 (0.34%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    1 / 292 (0.34%)
    0 / 126 (0.00%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Infection Pseudomonas
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 46 (0.00%)
    0 / 292 (0.00%)
    0 / 48 (0.00%)
    0 / 292 (0.00%)
    0 / 124 (0.00%)
    0 / 292 (0.00%)
    0 / 126 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Week (W) 24-Placebo W24-Placebo to 50 mg q4w due to EE or CO W24-Sirukumab 50 mg q4w W24-Placebo to 100 mg q2w due to EE or CO W24-Sirukumab 100 mg q2w W52-Placebo to 50 mg q4w due to EE or CO W52-Sirukumab 50 mg q4w W52-Placebo to 100 mg q2w due to EE or CO W52-Sirukumab 100 mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 294 (33.33%)
    10 / 46 (21.74%)
    109 / 292 (37.33%)
    6 / 48 (12.50%)
    135 / 292 (46.23%)
    43 / 124 (34.68%)
    147 / 292 (50.34%)
    57 / 126 (45.24%)
    162 / 292 (55.48%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 294 (2.38%)
    0 / 46 (0.00%)
    9 / 292 (3.08%)
    0 / 48 (0.00%)
    8 / 292 (2.74%)
    3 / 124 (2.42%)
    17 / 292 (5.82%)
    3 / 126 (2.38%)
    15 / 292 (5.14%)
         occurrences all number
    7
    0
    9
    0
    8
    3
    17
    3
    15
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    6 / 294 (2.04%)
    1 / 46 (2.17%)
    18 / 292 (6.16%)
    2 / 48 (4.17%)
    17 / 292 (5.82%)
    12 / 124 (9.68%)
    27 / 292 (9.25%)
    8 / 126 (6.35%)
    23 / 292 (7.88%)
         occurrences all number
    6
    1
    18
    2
    17
    12
    27
    8
    23
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    4 / 294 (1.36%)
    1 / 46 (2.17%)
    14 / 292 (4.79%)
    1 / 48 (2.08%)
    12 / 292 (4.11%)
    6 / 124 (4.84%)
    18 / 292 (6.16%)
    5 / 126 (3.97%)
    15 / 292 (5.14%)
         occurrences all number
    4
    1
    14
    1
    12
    6
    18
    5
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 294 (0.68%)
    0 / 46 (0.00%)
    7 / 292 (2.40%)
    0 / 48 (0.00%)
    13 / 292 (4.45%)
    3 / 124 (2.42%)
    13 / 292 (4.45%)
    4 / 126 (3.17%)
    22 / 292 (7.53%)
         occurrences all number
    2
    0
    7
    0
    13
    3
    13
    4
    22
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    4 / 294 (1.36%)
    2 / 46 (4.35%)
    22 / 292 (7.53%)
    1 / 48 (2.08%)
    41 / 292 (14.04%)
    5 / 124 (4.03%)
    28 / 292 (9.59%)
    19 / 126 (15.08%)
    47 / 292 (16.10%)
         occurrences all number
    4
    2
    22
    1
    41
    5
    28
    19
    47
    Injection Site Pruritus
         subjects affected / exposed
    2 / 294 (0.68%)
    1 / 46 (2.17%)
    5 / 292 (1.71%)
    0 / 48 (0.00%)
    28 / 292 (9.59%)
    4 / 124 (3.23%)
    8 / 292 (2.74%)
    10 / 126 (7.94%)
    31 / 292 (10.62%)
         occurrences all number
    2
    1
    5
    0
    28
    4
    8
    10
    31
    Injection Site Swelling
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 46 (4.35%)
    3 / 292 (1.03%)
    1 / 48 (2.08%)
    21 / 292 (7.19%)
    2 / 124 (1.61%)
    4 / 292 (1.37%)
    7 / 126 (5.56%)
    24 / 292 (8.22%)
         occurrences all number
    0
    2
    3
    1
    21
    2
    4
    7
    24
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 294 (1.02%)
    0 / 46 (0.00%)
    6 / 292 (2.05%)
    0 / 48 (0.00%)
    11 / 292 (3.77%)
    2 / 124 (1.61%)
    9 / 292 (3.08%)
    0 / 126 (0.00%)
    15 / 292 (5.14%)
         occurrences all number
    3
    0
    6
    0
    11
    2
    9
    0
    15
    Musculoskeletal and connective tissue disorders
    Rheumatoid Arthritis
         subjects affected / exposed
    28 / 294 (9.52%)
    2 / 46 (4.35%)
    13 / 292 (4.45%)
    1 / 48 (2.08%)
    15 / 292 (5.14%)
    12 / 124 (9.68%)
    30 / 292 (10.27%)
    4 / 126 (3.17%)
    30 / 292 (10.27%)
         occurrences all number
    28
    2
    13
    1
    15
    12
    30
    4
    30
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 294 (1.70%)
    0 / 46 (0.00%)
    6 / 292 (2.05%)
    0 / 48 (0.00%)
    11 / 292 (3.77%)
    6 / 124 (4.84%)
    13 / 292 (4.45%)
    4 / 126 (3.17%)
    22 / 292 (7.53%)
         occurrences all number
    5
    0
    6
    0
    11
    6
    13
    4
    22
    Nasopharyngitis
         subjects affected / exposed
    11 / 294 (3.74%)
    0 / 46 (0.00%)
    21 / 292 (7.19%)
    1 / 48 (2.08%)
    15 / 292 (5.14%)
    2 / 124 (1.61%)
    34 / 292 (11.64%)
    7 / 126 (5.56%)
    26 / 292 (8.90%)
         occurrences all number
    11
    0
    21
    1
    15
    2
    34
    7
    26
    Pharyngitis
         subjects affected / exposed
    9 / 294 (3.06%)
    3 / 46 (6.52%)
    6 / 292 (2.05%)
    0 / 48 (0.00%)
    5 / 292 (1.71%)
    4 / 124 (3.23%)
    9 / 292 (3.08%)
    3 / 126 (2.38%)
    10 / 292 (3.42%)
         occurrences all number
    9
    3
    6
    0
    5
    4
    9
    3
    10
    Sinusitis
         subjects affected / exposed
    8 / 294 (2.72%)
    1 / 46 (2.17%)
    11 / 292 (3.77%)
    0 / 48 (0.00%)
    7 / 292 (2.40%)
    4 / 124 (3.23%)
    14 / 292 (4.79%)
    3 / 126 (2.38%)
    15 / 292 (5.14%)
         occurrences all number
    8
    1
    11
    0
    7
    4
    14
    3
    15
    Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 294 (6.46%)
    0 / 46 (0.00%)
    19 / 292 (6.51%)
    0 / 48 (0.00%)
    12 / 292 (4.11%)
    4 / 124 (3.23%)
    24 / 292 (8.22%)
    9 / 126 (7.14%)
    26 / 292 (8.90%)
         occurrences all number
    19
    0
    19
    0
    12
    4
    24
    9
    26
    Urinary Tract Infection
         subjects affected / exposed
    11 / 294 (3.74%)
    0 / 46 (0.00%)
    4 / 292 (1.37%)
    0 / 48 (0.00%)
    14 / 292 (4.79%)
    1 / 124 (0.81%)
    13 / 292 (4.45%)
    6 / 126 (4.76%)
    19 / 292 (6.51%)
         occurrences all number
    11
    0
    4
    0
    14
    1
    13
    6
    19

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2012
    Clarification on the status of contraception of sexually active women; Clarification on the requirements for QuantiFERON-TB Gold test or purified protein derivative (PPD) test; Clarification of the exclusion criterion regarding the use of etanercept or yisaipu within 6 weeks of first study agent administration; Clarification that in the event of clinically significant decreases in neutrophils or platelet counts, methotrexate (MTX) should be temporarily or permanently discontinued; Clarification on the time period during which intra-articular (IA) steroid injections are allowed; Clarification on the training requirements for the independent joint assessor (IJA) and backup IJA was made; Questions added to the WLQ were removed; All events that met liver chemistry stopping criteria had to be reported as a serious adverse event (SAE); Text describing interruption of study agent administration was added; Clarification of hepatitis B virus (HBV) monitoring for subjects without detectable HBV deoxyribonucleic acid (DNA) at screening were made.
    26 Sep 2013
    Deletion of selected study site visits and allowance of subjects to self-administer study agent at home; Addition of the erythrocyte sedimentation rate (ESR) evaluation to the Screening visit assessments; Inclusion criterion was revised to: subjects must have a screening CRP level .8.00 mg/L or ESR .28 mm/hr; Retesting and rescreening procedures were revised to allow retesting of laboratory values or study entry procedure once; Exclusion criteria were modified to allow for shorter washout periods for a biologic prior to study entry, to clarify the procedure for detection of the M1 metabolite of leflunomide, if applicable; Clarification that subjects who have received the Bacille Calmette-Guerin vaccine within 12 months of screening were ineligible for the study; Clarification to Prohibitions and Restrictions that a woman must not donate eggs (ova,oocytes) for the purposes of assisted reproduction during the study and for 4 months after receiving the last dose of study agent; Clarification on the self-administration of study agent; Clarification on treatment compliance was added due to allowance of self-administration of study agent; Tofacitinib (XELJANZR) and any other biologic agent for the treatment of RA have been added to the list of prohibited medications; Clinic visits and self-administration schedules have been revised; The schedule for the collection of blood samples has been revised to match the revised studysite visit schedule; Clarification was made that all initial product quality complaints (PQCs) must be reported tothe Sponsor by the investigational staff within 24 hours after being made aware of the event; Clarifications on the transportation, storage, and administration of study agent by subjects who are able to self-administer the study agent at home were made; Clarification of HBV monitoring for subjects without detectable HBV DNA at screening was made.
    18 Feb 2014
    The total number of subjects to be enrolled was decreased from 990 to 840 subjects; The subject's name and date of birth were removed from the study card; Clarifications on the criteria for the planned statistical analyses of clinical laboratory data were made.
    09 May 2014
    Golimumab intravenous (IV) was added to list of anti-TNF agents that require a washout period prior to the first administration of study agent; Per data monitoring committee (DMC) recommendation, GI perforation and acute diverticulitis were added to the list of conditions that would result in the permanent discontinuation of study agent administrations; Introductory text was added and contents of the study card have been updated; Clarification was made that subject would be eligible for enrollment in the long term extension (LTE) provided a participating site is available to them; Clarification for subjects who do not participate in the LTE study was made; Clarification on the definition of end of study was made.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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